1. Field of the Invention
The present invention relates to a method of determining the dose and administration of statin.
2. Description of the Related Art
HMG-CoA reductase inhibitors (statins) are potent cholesterol-lowering drugs that are being widely used in clinical practice for the primary and secondary prevention of coronary artery diseases (see Referenced Patent Publications (RPPs) 1 and 2 as described hereinafter). Additionally, it has been reported in recent years that statins protectively act on cardiovascular diseases beyond their lipid-lowering action (so-called pleiotropic effects) and hence are currently being highlighted (see NPLs 3 and 4). The pleiotropic effects of statins could be mediated by reduced synthesis of isoprenoids that playa role of functioning for the post-translational regulation of intracellular proteins (see RPP 1). In other words, the activity of small GTP-binding proteins such as Rho, Rac and Ras, of which membrane localization and GTPase activity are dependent on isoprenylation of the proteins, is believed to mediate the pleiotropic effects of statins (see RPPs 5 and 6).
The present inventors have previously demonstrated that low-dose statins (atorvastatin and pravastatin, 20 mg day−1 for 1 week) significantly inhibit Racl activity only without suppressing the RhoA/Rho-kinase activity in circulating leucocytes in normal and healthy volunteers (see RPP 7). It is known that Racl plays a crucial role in generating reactive oxygen species (ROS). Since it has been reported that Racl increases ROS production and thereby develops myocardial hypertrophy and ventricular remodeling, it has been suggested that Racl may be an important mediator of cardiovascular hypertrophy (see RPP 8).
It has been reported that simvastatin inhibits Racl-mediated nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity in the heart and vascular smooth muscle in mouse models having angiotensin II (AngII)-induced cardiac hypertrophy (see RPPs 9 and 10). These findings are further supported by analysis of human heart tissues and it has been reported that statins suppress ROS production by way of Racl activation (see RPP 11). Thus, the present inventors have proposed that the pleiotropic effects of low-dose statins are mediated mainly through inhibition of the Racl pathway rather than that of the Rho/Rho-kinase pathway (see RPP 7).
The small GTP-binding protein GDP dissociation simulator (SmgGDS) is one belonging to the only guanine nucleotide exchange factor (GEF) in the armadillo (ARM) family of proteins (see RPPs 12 and 13). Recently, the role of GEF in the development of cardiovascular diseases has been highlighted (see RPPs 14 through 16). It has also been reported that purified SmgGDS interacts with the small GTPase C-terminal polybasic region (PBR) and activates RhoA and RhoC by its GEF function (see RPP 17). Furthermore, it has been reported that the PBR of Racl has a functional nuclear localization signal (NLS) sequence which is not present in RhoA (see RPP 13). Racl with the NSL will accompany SmgGDS into the nucleus and thereby be degraded by the proteasome system (see RPP 18).
Referenced Patent Publication (RPP) 1 is Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Survival Study (4S). Lancet 344, 1383-1389 (1994); RPP2 is Levine, G. N., Keaney, Jr., J. F. & Vita, J. A., N. Engl. J. Med. 332, 512-521 (1995); RPP3 is Davignon J., Circulation 109, 39-43 (2004); RPP4 is Rikitake, Y., Liao, J. K., Circ. Res. 97, 1232-1235 (2005); RPP5 is Hall, A., Science 279, 509-514 (1998); RPP6 is Takemoto, M., Liao JK., Arterioscler. Thromb. Vasc. Biol. 21, 1712-1719 (2001); RPP7 is Rashid M. et al., Circ. J. 73, 361-370 (2009); RPP8 is Brown J. H., Del Re, D. P., Sussman, M. A., Circ. Res. 98, 730-742 (2006); RPP9 is Takemoto M. et al., J. Clin. Invest. 108, 1429-1437 (2001); RPP10 is Wassmann, S. et al., Mol. Pharmacol. 59, 646-654 (2001); RPP11 is Maack, C. et al., Circulation 108, 1567-1574 (2003); RPP12 is Yamamoto, T. et al., J. Biol. Chem. 265, 16626-16634 (1990); RPP13 is Williams, C. L., Cell signal. 15, 1071-1080 (2003); RPP14 is Guilluy, C. et al., Nat. Med. 16, 183-190 (2010); RPP15 is Sauzeau, V., Sevilla, M. A., Montero, M. J. & Bustelo, X. R., J. Clin. Invest. 120, 315-330 (2010); RPP16 is Sauzeau, V. et al., Nat. Med. 12, 841-845 (2006); RPP17 is Hamel, B. et al., J. Biol. Chem. 286, 12141-12148 (2011); RPP18 is Lannning, C. C. et al., J. Biol. Chem. 279, 44197-44210 (2004).